Adhesives, wound dressings, anti-adhesion materials, hemostats, sealants, and spray kits

Abstract

This adhesive comprises a first agent, which comprises cyclodextrin and a gelatin derivative represented by formula 1: GltnNH-R1, which comprises a gelatin and a hydrophobic group bonded thereto through an imino group, and a second agent, which comprises a crosslinking agent for the gelatin derivative. The adhesive gives cured objects which are less apt to swell in physiological saline. In formula 1, Gltn represents a residue of the gelatin, R1 represents the hydrophobic group, and NH represents the imino group bonded to both the residue and the hydrophobic group.

Description

[Technical field]

[0001] The present invention relates to adhesives, wound dressings, adhesion inhibitors, hemostats, sealants, and spray kits. [Background technology]

[0002] A tissue adhesive using a gelatin derivative obtained by introducing a hydrophobic group into gelatin is known. Patent Document 1 describes "a tissue adhesive in which an adhesive component containing an aqueous solution of fish-derived gelatin and a hardening component containing an aqueous solution of water-soluble crosslinking molecules are mixed and applied to tissue, the tissue adhesive being characterized in that the molecular backbone of the water-soluble crosslinking molecules has an amide bond, an ethylene glycol unit, or a sugar chain, and has two or more active ester groups, acid anhydride, or aldehyde groups." [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2014 / 112208 Summary of the Invention [Problem to be solved by the invention]

[0004] The tissue adhesive has excellent adhesiveness to biological tissues and excellent biocompatibility, and is therefore expected to find great applications in the future. However, the present inventors have found that the cured product may swell in physiological saline, leaving room for improvement.

[0005] Generally, the site where a surgical adhesive is applied is rich in moisture such as exudate and blood, and when the adhesive (and its hardened product) absorbs the moisture and swells, the adhesive may peel off from the application site, for example, from a closed wound. Even if the adhesive does not peel off, it is expected that swelling will cause shear stress at the interface between the cured product and the biological tissue, which will increase the burden on the biological tissue. Therefore, it is preferable that the adhesive does not swell easily after curing.

[0006] Therefore, an object of the present invention is to provide an adhesive, the hardened product of which is unlikely to swell in physiological saline. Another object of the present invention is to provide a wound dressing, an adhesion preventing material, a hemostatic material, a sealant, and a spray kit. [Means for solving the problem]

[0007] As a result of extensive investigations aimed at achieving the above object, the present inventors have found that the above object can be achieved by the following configuration.

[0008] [1] An adhesive comprising a gelatin derivative having a hydrophobic group bonded to gelatin via an imino group, the gelatin derivative being represented by the formula 1 described below, a first agent containing cyclodextrin, and a second agent containing a crosslinker for the gelatin derivative.

[0009] Since the hardened adhesive does not easily swell in physiological saline, even after application to biological tissue, it is not likely to peel off from the biological tissue and is also not likely to cause stress at the interface, which tends to reduce the burden on the biological tissue to which the adhesive is applied.

[0010] [2] The adhesive according to [1], wherein the introduction rate of the hydrophobic group in the first agent is 5.0 to 80.0 mol %.

[0011] An adhesive having an introduction rate within the above range exhibits superior effects of the present invention.

[0012] [3] The adhesive according to [1] or [2], wherein the first agent contains a solvent, and the concentration of the gelatin derivative in the first agent is 0.010 to 0.300 g / mL.

[0013] An adhesive having a gelatin derivative concentration within the above range exhibits a more excellent effect of the present invention.

[0014] [4] The adhesive according to [3], wherein the concentration is greater than 0.050 g / mL and less than 0.150 g / mL.

[0015] If the concentration exceeds 0.050 g / mL, the resulting adhesive has better pressure resistance, whereas if the concentration is less than 0.150 g / mL, the cured product is less likely to swell in saline and has better pressure resistance.

[0016] [5] The adhesive according to [2], wherein the introduction rate is 10.0 to 50.0 mol %.

[0017] When the introduction rate is 10.0 mol % or more, the cured product is less likely to swell in physiological saline and has better pressure resistance, and when it is 50.0 mol % or less, the adhesive has better pressure resistance.

[0018] [6] The adhesive according to any one of [1] to [5], wherein the hydrophobic group contains a linear or branched alkyl group having 1 to 20 carbon atoms ("alkyl group A1").

[0019] When the hydrophobic group contains an alkyl group A1, the adhesive has better adhesive strength to biological tissue, and the viscosity of the first agent tends to be lower.

[0020] [7] R in Equation 1 below 1 The adhesive according to [6], wherein the alkyl group A2 is a straight-chain alkyl group having 7 to 12 carbon atoms.

[0021] R in Equation 1 below 1 When contains an alkyl group A2, the adhesive has even better adhesive strength to biological tissue, and the viscosity of the first agent also tends to be even lower.

[0022] [8] The adhesive according to any one of [1] to [7], wherein the cyclodextrin is α-cyclodextrin or a derivative thereof.

[0023] Since α-cyclodextrin easily includes alkyl groups (particularly alkyl groups A1 and A2), the viscosity of the first agent obtained as a result tends to be lower. In addition, the hardened product is less likely to swell in physiological saline.

[0024] [9] The adhesive described in any one of [1] to [8], wherein the molar ratio of the cyclodextrin content to the hydrophobic group content in the first agent (also referred to as "Cy / HBic") is 0.1 or more.

[0025] In the first agent of the adhesive having a Cy / HBic within the above numerical range, the amount of cyclodextrin relative to the hydrophobic groups of the gelatin derivative is likely to be sufficient, and as a result, the viscosity of the first agent of the resulting adhesive is likely to be lower, and the cured product is less likely to swell in saline.

[0026]

[10] The adhesive according to [9], wherein the molar ratio is greater than 2.6 and is 10 or less.

[0027] The first part of the adhesive having a Cy / HBic within the above numerical range tends to have a lower viscosity and is suitable as an adhesive for spraying.

[0028]

[11] The adhesive according to any one of [1] to

[10] , wherein the crosslinking agent is a compound having at least two active ester groups.

[0029] When the curable group of the crosslinking agent is an active ester group, it tends to react selectively with primary amino groups under mild conditions, resulting in superior properties as a room-temperature curing adhesive.

[0030]

[12] The adhesive according to any one of [1] to

[11] , wherein the gelatin is cold-water fish gelatin.

[0031] Cold-water fish gelatin has excellent fluidity at living body temperature, so adhesives made from cold-water fish gelatin as the raw material tend to have lower viscosity.

[0032]

[13] A wound dressing comprising the adhesive according to any one of [1] to

[12] .

[14] An anti-adhesion material comprising the adhesive according to any one of [1] to

[12] .

[15] A hemostatic material comprising the adhesive described in any one of [1] to

[12] .

[16] A sealant comprising the adhesive according to any one of [1] to

[12] .

[17] A spray kit comprising the adhesive according to any one of [1] to

[12] and a sprayer for the adhesive. Effect of the Invention

[0033] According to the present invention, an adhesive, the hardened product of which does not easily swell in physiological saline, can be provided. Also, according to the present invention, a wound dressing material, an adhesion preventing material, a hemostatic material, a sealant (sealing material), and a spray kit can be provided. [Brief description of the drawings]

[0034] [Figure 1] FIG. 2 is an explanatory diagram of components of a sprayer included in a spray kit according to an embodiment of the present invention. [Diagram 2] FIG. 2 is an illustration of an assembled spray kit. [Diagram 3] 13 is a flow chart illustrating a method of applying adhesive to a target tissue with a spray kit. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] The present invention will be described in detail below. The following description of the components may be based on a representative embodiment of the present invention, but the present invention is not limited to such an embodiment. In this specification, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits.

[0036] In the description of groups (atomic groups) in this specification, the description that does not indicate whether substituted or unsubstituted includes both unsubstituted and substituted groups, as long as it does not impair the effects of the present invention. For example, "alkyl group" includes not only alkyl groups that do not have a substituent (unsubstituted alkyl groups), but also alkyl groups that have a substituent (substituted alkyl groups). This also applies to each compound.

[0037] [glue] The adhesive according to the embodiment of the present invention comprises a gelatin derivative in which a hydrophobic group is bonded to gelatin via an imino group, which is represented by the formula 1 described below, a first agent containing cyclodextrin, and a second agent containing a crosslinking agent for the gelatin derivative. The components contained in the adhesive according to the embodiment (hereinafter also referred to as the present adhesive) will be described in detail below.

[0038] <First agent> The first agent according to this embodiment contains a gelatin derivative and a cyclodextrin, and may further contain a solvent. The first agent is mixed with the second agent described below, and the gelatin derivative is crosslinked by the crosslinking agent to form the skeleton of the hardened material. The hardening reaction is typically a reaction between the primary amino group of the hydrophobized gelatin and the crosslinkable group (typically an active ester group, etc.) of the second agent.

[0039] In this regard, the content of the first agent in the adhesive is preferably prepared so that, in relation to the content of crosslinkable groups in the second agent described below, the content of crosslinkable groups in the second agent is 0.1 to 3.0 equivalents per equivalent of amino groups in the first agent, more preferably 0.2 to 2.0 equivalents, even more preferably 0.3 to 1.5 equivalents, and particularly preferably 0.3 to 0.8 equivalents.

[0040] (gelatin derivatives) The content of the gelatin derivative in the first agent is not particularly limited, but the concentration of the gelatin derivative in the first agent (gelatin derivative / solvent, rounded to the third decimal place) is preferably 0.010 to 0.300 g / mL, more preferably more than 0.050 g / mL, even more preferably 0.075 g / mL or more, particularly preferably more than 0.075 g / mL, preferably 0.150 g / mL or less, more preferably less than 0.150 g / mL, and particularly preferably 0.100 g / mL or less. When two or more gelatin derivatives are used in combination, the total content thereof is preferably within the above numerical range.

[0041] When the concentration of the gelatin derivative is more than 0.050 g / mL, an adhesive having better pressure resistance is obtained. When the concentration of the gelatin derivative is less than 0.150 g / mL, the cured product is less likely to swell, and an adhesive having better pressure resistance is obtained. When the concentration of the gelatin derivative is 0.075 g / mL or more, an adhesive having even better pressure resistance is obtained. When the concentration of the gelatin derivative is 0.100 g / mL or less, the cured product is even less likely to swell, and an adhesive having even better pressure resistance is obtained.

[0042] The gelatin derivative is a gelatin derivative in which a hydrophobic group is bonded to gelatin via an imino group (i.e., --NH--), and is represented by formula 1. Formula 1: GltnNH-R 1

[0043] In formula 1, Gltn represents a gelatin residue, and NH represents an imino group bonded to the gelatin residue and a hydrophobic group.

[0044] In formula 1, R 1 represents a hydrophobic group. The hydrophobic group is not particularly limited, but is preferably a group having a hydrocarbon group having 1 to 20 carbon atoms. Here, a group having a hydrocarbon group having 1 to 20 carbon atoms means a hydrocarbon group having 1 to 20 carbon atoms itself, and a group containing a hydrocarbon group having 1 to 20 carbon atoms and a linking group.

[0045] That is, L is a single bond or a divalent linking group, and R 21 When is a hydrocarbon group having 1 to 20 carbon atoms, the hydrophobic group is *-LR 21 A group represented by the following formula is preferred: In addition, * represents the bonding position.

[0046] Examples of the divalent linking group for L include -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -N(R)- (R represents a hydrogen atom or a monovalent organic group (preferably a hydrocarbon group having 1 to 20 carbon atoms)), an alkylene group (preferably an alkylene group having 2 to 10 carbon atoms), an alkenylene group (preferably an alkenylene group having 2 to 10 carbon atoms), and combinations thereof. Of these, -O-, -C(O)-, and -C(O)O- are preferred. In addition, when L contains a carbon atom, L and R 21 The total number of carbon atoms is preferably 1 to 20, more preferably 4 to 18, further preferably 6 to 14, and particularly preferably 7 to 12.

[0047] Examples of the hydrocarbon group having 1 to 20 carbon atoms include a chain hydrocarbon group having 1 to 20 carbon atoms, an alicyclic hydrocarbon group having 3 to 20 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and groups combining these.

[0048] Examples of the chain hydrocarbon group having 1 to 20 carbon atoms include linear or branched alkyl groups, with linear hydrocarbon groups being preferred. As the linear or branched alkyl group, A methyl group with one carbon atom; An ethyl group with two carbon atoms; Propyl and isopropyl groups with three carbon atoms; butyl, isobutyl, tert-butyl, and sec-butyl groups with four carbon atoms; C5 groups: pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl; C6 groups: hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl; The following are carbon numbers of 7: heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1,2,2-trimethylbutyl, 1,1,2-trimethylbutyl, 1,3,3-trimethylbutyl, 1,1,3-trimethylbutyl, 2,2,3-trimethylbutyl, and 2,3,3-trimethylbutyl; C8 octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 1-propylpentyl, 2-propylpentyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 5,5-dimethylhexyl, 3-ethyl-3-methylpentyl, 1,1-diethylbutyl, 2,2-diethylbutyl, 1,1,2,2-tetramethylbutyl, 1,1,3,3-tetramethylbutyl, 2,2,3,3-tetramethylbutyl, 1,1-dimethyl-2-ethylbutyl; Nonyl group, 2-methyloctyl group, 3-methyloctyl group, 4-methyloctyl group, 2,2-dimethylheptyl group, 2,3-dimethylheptyl group, 2,4 dimethylheptyl group, 2,6 dimethylheptyl group, 3,3 dimethylheptyl group, 3,4 dimethylheptyl group, 3,5 dimethylheptyl group, 4,4 dimethylheptyl group, 3-ethylheptyl group, 4-ethylheptyl group, 2,2,3-trimethylhexyl group, 2,2,4-trimethylhexyl group, 2,2,5-trimethylhexyl group, 2,3,3-trimethylhexyl group, 2,3,4-trimethylhexyl group, 2,3,5-trimethylhexyl group, trimethylhexyl group, 2,4,4-trimethylhexyl group, 3,3,4-trimethylhexyl group, 2-methyl-3-ethylhexyl group, 3-methyl-3-ethylhexyl group, 3-ethyl-4-methylhexyl group, 3-ethyl-5-methylhexyl group, 2,2,3,3-tetramethylpentyl group, 2,2,3,4-tetramethylpentyl group, 2,2,4,4-tetramethylpentyl group, 2,3,3,4-tetramethylpentyl group, 2,2-dimethyl-3-ethylpentyl group, 2,3-dimethyl-3-ethylpentyl group, 2,4-dimethyl-3-ethylpentyl group, 3,3-diethylpentyl group; Examples of the alkyl group having 10 carbon atoms include a decyl group, a 2-methylnonyl group, a 2-ethyloctyl group, a 2-propylheptyl group, and a 2-butylhexyl group.

[0049] In addition to the above, examples of the alkyl group include an undecyl group, a dodecyl group, a dodecyl group, a dodecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, and an icosyl group.

[0050] Examples of the alicyclic hydrocarbon group having 3 to 20 carbon atoms include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group, and a norbornyl group.

[0051] The aromatic hydrocarbon group having 6 to 14 carbon atoms is not particularly limited, but examples thereof include a phenyl group, a tolyl group, and a naphthyl group.

[0052] The group obtained by combining the above is not particularly limited, but examples thereof include aralkyl groups having 6 to 12 carbon atoms, such as a benzyl group, a phenethyl group, a naphthylmethyl group, and a naphthylethyl group.

[0053] Also, R 1 may be a group represented by the following formula: In the following formula, * represents the bonding position.

[0054] [ka]

[0055] In formula 1, the nitrogen atom (N) directly bonded to the residue of gelatin is derived from the ε-amino group of lysine (Lys) in gelatin. The NH structure of formula 1 is, for example, at 3300 cm in the FT-IR (Fourier transform infrared spectrometer) spectrum. -1 It can be detected by nearby bands.

[0056] The gelatin derivative represented by formula 11 is preferred in that it provides an adhesive having a more excellent effect of the present invention. Formula 11: GltnNH-CHR 2 R 3 In the above formula 11, R 2 represents a hydrocarbon group having 1 to 19 carbon atoms, and specific examples thereof include R 1 Among the hydrocarbon groups, the same groups as those of the hydrocarbon groups having 1 to 19 carbon atoms can be mentioned, and the preferred embodiments are also the same. R 3 represents a hydrocarbon group having 1 to 19 carbon atoms or a hydrogen atom, and a hydrogen atom is preferable. 2 , and R 3 The total number of carbon atoms is not particularly limited, but is preferably 2 to 19, more preferably 3 to 17, further preferably 5 to 13, and particularly preferably 6 to 11.

[0057] The introduction rate of the hydrophobic group in the first agent is not particularly limited, but is preferably 5.0 to 80.0 mol %, more preferably 10.0 mol % or more, and more preferably 50.0 mol % or less. The introduction rate of hydrophobic groups is a value defined as the imino group content in the first agent / (imino group content+amino group content), and is a value obtained by quantifying the amount of amino groups using the 2,4,6-trinitrobenzenesulfonic acid method.

[0058] In addition, the "introduction rate of hydrophobic groups in the first agent" is synonymous with the introduction rate of hydrophobic groups in a gelatin derivative when the first agent does not contain gelatin other than the gelatin derivative (for example, raw material gelatin). On the other hand, for example, when the first agent contains a gelatin derivative and a raw material gelatin described later (in other words, when it is a mixture containing each of a gelatin derivative and raw material gelatin), the introduction rate of the hydrophobic group is a value that reflects the total amount of amino groups possessed by the gelatin derivative and raw material gelatin. Specifically, the introduction rate of the hydrophobic group in the first agent can also be calculated by the following formula A.

[0059] Formula A: introduction rate of hydrophobic group in first agent = Ha × Ma / (Ma + Mb) In the formula, Ma and Mb represent the mass-based contents of the gelatin derivative and gelatin in the first agent, respectively, and Ha represents the introduction rate of the hydrophobic group in the gelatin derivative.

[0060] When the introduction rate of hydrophobic groups in the first part is 10.0 mol % or more, the cured product becomes less susceptible to swelling, and when it is 50.0 mol % or less, an adhesive having superior pressure resistance strength can be obtained.

[0061] -Method of manufacturing gelatin derivatives The method for producing the gelatin derivative is not particularly limited, and any known method can be used. For example, a method of reacting an ε-amino group of gelatin with an aldehyde or ketone to bind a hydrophobic group via a Schiff base, and reducing the Schiff base to obtain a gelatin derivative is exemplified. This method is described, for example, in paragraphs 0029 to 0031 of JP 2019-216755 A.

[0062] According to the above method, a gelatin derivative (formula: GltnNH-R) in which a hydrophobic group is directly bonded to a gelatin residue via an imino group is obtained. 1 ) is obtained. The hydrophobic group is derived from an aldehyde or a ketone.

[0063] Another method is to react an acid halide or a chloroformate compound with an ε-amino group of gelatin in the presence of a base such as triethylamine to obtain an amide, which is described in, for example, paragraphs 0072 to 0080 of WO 2014 / 112208.

[0064] According to the above method, a gelatin derivative is obtained in which a hydrophobic group is bonded to a gelatin residue via an amide bond (including an imino group). The hydrophobic group is derived from an acid halide or a chloroformate compound.

[0065] When a large excess of a poor solvent, for example cold ethanol, is added to the reaction solution obtained above, the gelatin derivative precipitates, which is then filtered off and dried to obtain a powdered gelatin derivative. The gelatin derivative may be washed with ethanol or the like before drying.

[0066] The raw material gelatin used in the production of gelatin derivatives (hereinafter also referred to as "ORG gelatin") is typically gelatin without hydrophobic groups introduced therein (non-derivatized).

[0067] The molecular weight of ORG gelatin is not particularly limited, and generally, the weight average molecular weight is preferably 10,000 to 300,000. In one embodiment, it is also preferable that the molecular weight is less than 50,000 from the viewpoint of easily suppressing allergic reactions to the living body. In this respect, the molecular weight of gelatin is preferably 45,000 or less, more preferably 40,000 or less. There is no particular lower limit, but it is preferably 10,000 or more from the viewpoint that the cured product of the adhesive has superior mechanical strength.

[0068] The ORG gelatin can be any gelatin obtained by natural origin, chemical synthesis, fermentation, genetic recombination, etc., without any particular limitation. Among them, natural gelatin is preferred. Examples of natural gelatin include gelatin derived from mammals such as cows and pigs, and gelatin derived from fish such as sea bream, sturgeon, salmon, and cod.

[0069] When the adhesive is used as a liquid, it preferably has excellent fluidity at the temperature of use (eg, living body temperature) from the standpoint of ease of handling. In this respect, the ORG gelatin is preferably fish-derived gelatin, and in particular, gelatin derived from cold-water fish such as salmon and Alaska pollock. In addition, "using as a liquid" means that either the first agent or the second agent, or both, are liquids containing a solvent, or that both the first agent and the second agent are solids that are mixed with a solvent at the time of use.

[0070] Fish-derived gelatin, particularly cold-water fish gelatin, preferably has 80 or less hydroxyproline-derived units and / or 110 or less proline-derived units per 1000 amino acids as constituent units. Gelatin satisfying these conditions has better fluidity at room temperature, and therefore, when used in the first agent (as a raw material for gelatin derivatives and / or as an additive), an adhesive with excellent handleability can be obtained.

[0071] The ORG gelatin may be either acid-processed gelatin or alkali-processed gelatin. The first agent may contain two or more different types of gelatin as the ORG gelatin. The two or more different types mean that one or more of origin, molecular weight, processing method, etc. are different.

[0072] (Cyclodextrin) Cyclodextrin is a cyclic compound in which D-glucose units are bonded in a ring shape via α-1,4-glucosidic bonds, and is produced by the action of an enzyme such as cyclodextrin glucanotransferase on starch and / or a starch hydrolysate.

[0073] The content of cyclodextrin in the first agent is not particularly limited, but the concentration of cyclodextrin in the first agent (cyclodextrin / solvent, rounded to the third decimal place) is preferably 0.001 to 0.200 g / mL, more preferably 0.003 to 0.150 g / mL. When two or more types of cyclodextrin are used in combination, the total content thereof is preferably within the above-mentioned numerical range.

[0074] Furthermore, in order to obtain an adhesive having even better effects of the present invention, the molar ratio of the cyclodextrin content to the hydrophobic group content in the first agent (cyclodextrin / hydrophobic group, "Cy / HBic") is preferably 0.1 or more, more preferably 1.0 or more, even more preferably greater than 1.0, particularly preferably greater than 2.0, most preferably greater than 2.5, and is preferably 10.0 or less, more preferably 8.0 or less, and even more preferably 6.0 or less. When two or more types of cyclodextrin are used in combination, the total content thereof is preferably within the above-mentioned numerical range.

[0075] When Cy / HBic exceeds 1.0, the viscosity of the first agent tends to be lower, which is preferable for an adhesive to be sprayed. When Cy / HBic exceeds 2.0, the viscosity tends to be lower still, and this tendency is particularly noticeable when it exceeds 2.5.

[0076] It is considered that cyclodextrin also includes gelatin residues other than hydrophobic groups, and that there is a negative correlation between the concentration of cyclodextrin in the first agent and the viscosity of the first agent. From the viewpoint of a more significant effect of reducing the viscosity of the added cyclodextrin, Cy / HBic is, in one embodiment, preferably 10.0 or less, more preferably 8.0 or less, and even more preferably 6.0 or less.

[0077] As the cyclodextrin, cyclodextrins having six glucose units (α type), seven glucose units (β type), eight glucose units (γ type), etc. can be used, and further, derivatives thereof can also be used (or used in combination). Among these, α-cyclodextrin or a derivative thereof is preferred since the size of its cavity is more suitable for inclusion of a hydrophobic group.

[0078] Examples of α-cyclodextrin derivatives include methyl α-cyclodextrin, butyl α-cyclodextrin, 2-hydroxypropyl α-cyclodextrin, acetyl α-cyclodextrin, succinyl α-cyclodextrin, glucosyl α-cyclodextrin, maltosyl α-cyclodextrin, α-cyclodextrin carboxymethyl ether, phosphate α-cyclodextrin, and carboxymethyl α-cyclodextrin.

[0079] Examples of β-cyclodextrin derivatives include methyl-β-cyclodextrin (MBCD), (2-hydroxypropyl)-β-cyclodextrin (HPBCD), carboxymethyl-β-cyclodextrin, carboxymethyl-ethyl-β-cyclodextrin, diethyl-β-cyclodextrin, dimethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, hydroxybutenyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, maltosyl-β-cyclodextrin, random methyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, 2-selenium-bridged-β-cyclodextrin, and 2-tellurium-bridged-β-cyclodextrin.

[0080] Examples of γ-cyclodextrin derivatives include 2-hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, butyl-γ-cyclodextrin, 3A-amino-3A-deoxy-(2AS,3AS)-γ-cyclodextrin, mono-2-O-(p-toluenesulfonyl)-γ-cyclodextrin, mono-6-O-(p-toluenesulfonyl)-γ-cyclodextrin, mono-6-O-mesitylenesulfonyl-γ-cyclodextrin, octakis(2,3,6-tri-O-methyl)-γ-cyclodextrin, octakis(2,6-di-O-phenyl)-γ-cyclodextrin, octakis(6-Ot-butyldimethylsilyl)-γ-cyclodextrin, and octakis(2,3,6-tri-O-acetyl)-γ-cyclodextrin.

[0081] (solvent) The first agent may further contain a solvent. Examples of the solvent include aqueous solvents, and examples of the aqueous solvent that can be used include ultrapure water; physiological saline; various inorganic salt buffers such as boric acid, phosphoric acid, and carbonate; and mixtures thereof. Among them, the aqueous solvent is preferably a boric acid buffer solution having a pH of 8 to 13, and more preferably a boric acid buffer solution having a pH of 9 to 12. The aqueous solvent is preferably used in an amount such that the solid content of the first agent is 0.050 to 0.800 g / mL.

[0082] In addition to the above, the first agent may contain ORG gelatin explained as raw material gelatin.

[0083] <Second agent> The second agent includes a crosslinking agent for the gelatin derivative. The second agent may also include a solvent.

[0084] (Crosslinking agent) The crosslinking agent is typically a compound having at least two substituents (crosslinkable groups) in one molecule that can react with the primary amino groups of the gelatin derivative. When the first agent contains ORG gelatin, the primary amino groups of the ORG gelatin also react with the crosslinking agent.

[0085] The crosslinking group of the crosslinking agent is not particularly limited, but an active ester group (activated ester group) is preferred from the viewpoint of being easily selectively reactive under mild conditions with a primary amino group (typically derived from a gelatin derivative) in the first agent. That is, as the crosslinking agent, a compound having at least two active ester groups in one molecule is preferred. Such cross-linking agents include polybasic acids activated with N-hydroxysuccinimide or N-hydroxysulfosuccinimide.

[0086] In addition to the above, genipin, aldehyde compounds, acid anhydrides, dithiocarbonates, diisothiocyanates, and the like can be used as crosslinking agents.

[0087] Examples of polybasic acids include tartaric acid, citric acid, malic acid, glutaric acid, glutamic acid, aspartic acid, oxaloacetic acid, cis-aconitic acid, 2-ketoglutaric acid, polytartaric acid, polycitric acid, polymalic acid, polyglutamic acid, polyaspartic acid, carboxymethylated dextrin, carboxymethylated dextran, carboxymethylated starch, carboxymethylated cellulose, carboxymethylated chitosan, and carboxymethylated pullulan.

[0088] As the crosslinking agent, disuccinimidyl glutarate (DSG), disuccinimidyl suberate (DSS), disuccinimidyl tartrate (DST), etc. can also be used.

[0089] Also, polybasic acid esters of polyethylene glycol or polyethylene glycol ether, in which at least one of the carboxyl groups in the polybasic acid that has not reacted with polyethylene glycol is converted into an active ester, such as 4,7,10,13,16-pentaoxanonadecanedioic acid di(N-succinimidyl) and polyethylene glycol di(succinimidyl succinate) (SS-PEG-SS) represented by the following formula:

[0090] [ka]

[0091] (n is a number that results in a number average molecular weight of approximately 20,000); Furthermore, pentaerythritol-polyethylene glycol ether tetrasuccinimidyl glutarate (4S-PEG) represented by the following formula:

[0092] [ka]

[0093] (n is a number such that Mw is about 3,000 to 30,000, preferably 5,000 to 27,000, and more preferably 15,000 to 25,000); etc. are also preferred.

[0094] Examples of the aldehyde compound include formyl group-introduced polysaccharides having two or more formyl groups introduced into one molecule, such as formyl group-introduced starch, formyl group-introduced dextran, formyl group-introduced dextrin, and formyl group-introduced hyaluronic acid.

[0095] Examples of the acid anhydride include glutaric anhydride, maleic anhydride, and succinic anhydride. Moreover, the diisothiocyanate may, for example, be hexamethylene diisothiocyanate. As the crosslinking agent, activated polyethylene glycol polybasic acid esters, formyl group-introduced polysaccharides, and the like are preferred, and activated polyethylene glycol polybasic acid esters are more preferred.

[0096] The content of the crosslinking agent in the second agent and the content of the second agent in the adhesive may be appropriately adjusted according to the content of amino groups in the first agent.

[0097] For example, relative to 1 equivalent of the amount of amino groups in the first agent, the amount of ester groups activated with N-hydroxysuccinimide (active ester groups) is preferably 0.1 to 3.0 equivalents, more preferably 0.2 to 2.0 equivalents, even more preferably 0.3 to 1.5 equivalents, and particularly preferably 0.3 to 0.8 equivalents. The second agent may contain one type of crosslinking agent alone or two or more types. When the second agent contains two or more types of crosslinking agents, the total content thereof is preferably within the above numerical range.

[0098] (solvent) The second agent may contain a solvent, preferably an aqueous solvent. As the aqueous solution, those already explained as the aqueous solution that the first agent may contain can be used.

[0099] Among these, a phosphate buffer solution having a pH of 3 to 8 is preferred, and a phosphate buffer solution having a pH of 4 to 6 is more preferred. It is preferable that the ionic strength of both aqueous solvents is adjusted so that the pH is about 8 to about 10 when the first agent containing a solvent and the second agent containing a solvent are mixed in equal volumes. For example, by using a borate buffer solution having a pH of 9 and an ionic strength of 0.05 to 0.1 as the first agent and a phosphate buffer solution having a pH of 4 and an ionic strength of 0.01 to 0.03 as the second agent, the pH can be set within the above range when mixed in equal volumes. Alternatively, the first agent may be a borate buffer solution having a pH of 10 and an ionic strength of 0.05 to 0.1, and the second agent may be a phosphate buffer solution having a pH of 4 and an ionic strength of 0.01 to 0.07.

[0100] <Additives> The first agent and / or the second agent may further contain various additives in amounts that do not impair the object of the present invention. Examples of additives include colorants, pH adjusters, and preservatives. For example, a colorant (e.g., brilliant blue) may be added to the first agent and / or the second agent so that the application location of the adhesive can be easily identified. The amount of the colorant added may be, for example, 10 to 100 μg / mL.

[0101] In addition, since the adhesive of the present invention (particularly the first agent) has a low viscosity, it is preferably used in the form of a mist sprayed from a sprayer for application; however, by adding a viscosity adjuster, the viscosity can be easily increased and dripping of the coating film before hardening can be suppressed. Therefore, the adhesive has the advantage that the viscosity can be adjusted according to the application site and use (the initial viscosity is low, so there is room for thickening).

[0102] The adhesive contains a gelatin derivative in which a hydrophobic group has been introduced into gelatin, but so long as it contains a gelatin derivative, it may also contain "other" gelatin and / or "other" gelatin derivatives. That is, when the first agent contains a derivative of Alaska pollock gelatin, the first agent may contain, for example, Alaska pollock gelatin, porcine gelatin, and / or a porcine gelatin derivative.

[0103] [Adhesive manufacturing method] This adhesive can be obtained by separately preparing the first and second parts. The methods for preparing the first and second parts are described below.

[0104] <Preparation method of the first agent> The first agent can be produced by mixing a gelatin derivative, a cyclodextrin, and other components as necessary. In this case, it is preferable to have a step of including at least a part of the hydrophobic group of the gelatin derivative in the cyclodextrin (forming an inclusion compound).

[0105] The method for including the hydrophobic group of the gelatin derivative with cyclodextrin is not particularly limited, and examples that can be used include a method in which the gelatin derivative is added to a slurry prepared by adding water to cyclodextrin and then mixed, and a method in which the cyclodextrin and the gelatin derivative are dissolved in a solvent and then dried.

[0106] In the case of the method of dissolving cyclodextrin and gelatin derivative in a solvent and drying, the first agent obtained is in a powder form. When this is used as a liquid first agent, an aqueous solvent such as a borate buffer solution may be added to the powder first agent. If necessary, additives may be added at this point. The obtained first agent can be filled into a predetermined container, such as a dispenser made of plastic such as polypropylene. When used as a tissue adhesive, it is preferable to fill an aqueous solution of the first agent into one of a double syringe type dispenser or the like, which is used when applying to tissue and can mix the two agents at the tip.

[0107] <Preparation method of the second agent> The second agent contains a crosslinking agent. The crosslinking agent may be synthesized by a known method, or a commercially available one may be used. When the second agent is liquid, the crosslinking agent may be mixed with an aqueous solvent, such as a phosphate buffer, for dissolving the crosslinking agent.

[0108] <How to apply this to your organization> The adhesive can be applied to incisions, skin wounds, and the like in a variety of surgical procedures, including respiratory surgery, digestive surgery, cardiovascular surgery, neurosurgery, and oral surgery.

[0109] By mixing the two parts, a curing reaction immediately occurs to form a cured product. The temperature during the curing reaction is not particularly limited, but is generally preferably 15 to 45° C., more preferably 20 to 42° C. The curing time is not particularly limited, but sufficient adhesive strength and film strength can be obtained in 1 to 60 minutes.

[0110] The adhesive can be used as a wound dressing for covering wounds in living tissues, and can also be used as an adhesion barrier for preventing postoperative adhesions.

[0111] Furthermore, since the cured product of this adhesive has both excellent tissue adhesion and flexibility, it can be used as a hemostatic material to stop bleeding from a vascular anastomosis, for example, by applying it to the vascular anastomosis. Furthermore, as described below, when applied to tissue, the adhesive has excellent pressure resistance, so it can withstand blood pressure, and its flexibility allows it to follow the pulsation of blood vessels. Furthermore, since the cured product of this adhesive has excellent adhesive properties as well as excellent absorbency and biocompatibility, it can also be used, for example, as a sealant to fill the gap between the dura mater, the dura mater suture, or the gap between the dura mater formation material and the dura mater when suturing the dura mater.

[0112] There are no particular limitations on the method of use of this adhesive, but it is preferable to apply it to the target site (tissue) using a sprayer, which will be described later, and allow a hardened product (gel) to form on the tissue.

[0113] [Spray kit] A spray kit according to an embodiment of the present invention includes a sprayer, a first agent, and a second agent, and is used to apply a mist of adhesive mixed with the first agent and the second agent to a target biological tissue, etc.

[0114] FIG. 1 is an illustration of the sprayer components included in the spray kit, and FIG. 2 is an illustration of the assembled spray kit.

[0115] The sprayer 10 has a first agent syringe consisting of an outer cylinder 15 and a plunger 18 with a gasket at its tip, and a second agent syringe consisting of an outer cylinder 14 and a plunger 17 with a gasket at its tip. Typically, the same amount of a first agent 21 and a second agent 22 are injected into each syringe. In FIG. 2, the first agent 21 is colored and the second agent 22 is not colored, but the second agent 22 may be colored, or neither may be colored.

[0116] External cylinders 14 and 15 are supported by syringe holder 16 in a restrained state so that they do not move, and applicator 13 is fitted and inserted into the tip. Inside applicator 13, flow paths (not shown) for first agent 21 and second agent 22 are formed, respectively, and the first agent and second agent pushed out from each syringe flow to the tip of applicator 13 without being mixed. Note that an internal flow path may be formed so that the first agent and second agent are mixed inside the applicator.

[0117] A plunger cap 19 is fitted to the rear end of the plunger 17 and the plunger 18. By pushing this plunger cap 19 toward the syringe holder 16, the two plungers 17, 18 can be pushed in as a unit, and the first agent 21 and the second agent 22 in the syringe can be pushed out in equal amounts.

[0118] The first agent and the second agent are pushed out from the syringe and passed through the flow passage in the applicator 13, and then passed through the flow passage in the extender 12 and are discharged in the form of a mist from the spray tip 11. Although the sprayer 10 has an extender 12, the sprayer 10 does not necessarily have to have the extender 12. If the sprayer 10 does not have the extender 12, the spray tip 11 may be connected to the outlet of the applicator 13.

[0119] Next, a method of using the spray kit will be described. Figure 3 is a flow chart illustrating a method of applying adhesive to target tissue by the spray kit. First, in step S30, the first agent and the second agent are prepared. The method of preparing the first agent and the second agent is not particularly limited, but may be, for example, a method of adding a predetermined amount of solvent to the first agent and the second agent, each of which does not contain a solvent, and then mixing them.

[0120] More specifically, the spray kit may include a vial containing powdered first agent and second agent, and a predetermined amount of solvent is injected into each vial to prepare liquid first agent and second agent. Note that these solvents may be injected in advance into the first agent syringe and the second agent syringe, respectively.

[0121] Next, in step S31, the prepared liquid first agent and second agent are injected into the respective syringes, and the sprayer is assembled. Specifically, the mixture prepared in the vial is sucked into each syringe, and then the sprayer is assembled.

[0122] Next, in step S32, the plunger cap is pushed in, causing a mist of adhesive to be discharged from the spray tip. This step applies the adhesive to the target tissue and quickly hardens into a gel. The hardened adhesive obtained by mixing the above-mentioned first and second agents has the characteristic of being resistant to swelling in saline solution, and therefore is less likely to peel off even in environments containing a large amount of moisture such as exudates and blood, and is less likely to generate stress at the interface, thereby reducing the burden on biological tissue. EXAMPLES

[0123] The present invention will be described below with reference to examples, but the present invention is not limited to these.

[0124] (1) Preparation of gelatin derivative "18C10" 10 g of alkaline-processed gelatin derived from Alaska pollock (Mw=37000, "B-Matrix Fish Gelatin TA (trade name)", manufactured by Nitta Gelatin, hereafter referred to as "Org gelatin") was added to 50 mL of ultrapure water-ethanol mixed solvent in an eggplant-shaped flask immersed in an oil bath at 50°C, and dissolved while stirring for about 2 hours to prepare a 20% by mass aqueous solution. Next, 1.5 times the equivalent of the decanal added later, picoline borane (manufactured by Junsei Chemical), was added to the resulting aqueous solution, and then decanal (manufactured by Tokyo Chemical Industry Co., Ltd.) was added in an amount of 0.5 times the equivalent of the amino groups of gelatin (molar ratio of decanal to 1 mole of amino groups of gelatin).

[0125] Next, a reflux condenser was attached to the eggplant-shaped flask, and the mixture was reacted at 55°C for 18 hours while stirring. The reaction solution was then dropped into 1L of ethanol to cause reprecipitation. After stirring for 1 hour, the mixture was left to stand in a freezer for 1 hour, and then filtered through a glass filter. The filtration residue was again placed in 1L of ethanol in a beaker to cause reprecipitation, and after stirring for 1 hour, the mixture was left to stand in a freezer for 1 hour. After filtering again through a glass filter, the filtration residue was dried in a vacuum dryer for more than one night, and a gelatin derivative in which a hydrophobic group, a decyl group (C10), was introduced into the gelatin residue via an imino group was obtained in a yield of 98%.

[0126] The introduction rate of decyl groups in the obtained gelatin derivative was determined by the following method. First, Org gelatin and gelatin derivatives were each mixed at 0.1 mass / volume%. The solution was dissolved in a water / DMSO (dimethyl sulfoxide) mixed solvent (volume ratio 1:1, same below) and dispensed in 100 μL portions into a 48-well plate. 100μL of 0.1% volume / volume triethylamine (TEA, Nacalai Tesque) dissolved in water / DMSO mixed solvent was added and stirred at 400 rpm for 1 minute on a plate shaker. 100μL of 0.1% mass / volume trinitrobenzenesulfonic acid (TNBS, Wako Pure Chemical Industries, Ltd.) dissolved in water / DMSO mixed solvent was added and stirred at 400 rpm for 1 minute on a plate shaker. After being shielded from light with aluminum foil and left to stand in a 37℃ incubator for 2 hours, the plate was removed from the incubator and 50μL of HCl (6mol / L) was added to stop the reaction, and the plate was stirred at 400 rpm for 1 minute on a plate shaker. After being shielded from light and left to stand for 10 minutes, the absorbance (Abs) at 340 nm was measured using an absorption spectrometer (TECAN, Spark 10M-NMST). The absorbance of a blank sample, which differs only in that it does not contain gelatin, was subtracted from the measured absorbance, and the introduction rate of decyl groups in the gelatin derivative was found to be 18.0 mol % using the following formula. Introduction rate (mol%) = [Abs (raw gelatin) - Abs (gelatin derivative) ] / [Abs(Organ gelatin)]×100

[0127] The gelatin derivative obtained by the above method was named "18C10."

[0128] In the same manner as above, except that the amount of decanal added was 0.1 equivalent, "7.8C10" having an introduction rate of decyl groups of 7.8 mol % was obtained. Moreover, in the same manner as above except that the amount of decanal added was 1.0 equivalent, "31C10" having an introduction rate of decyl groups of 31.0 mol% was obtained. Moreover, in the same manner as above except that the amount of decanal added was 2.0 equivalents, "51C10" having an introduction rate of decyl groups of 51.0 mol% was obtained.

[0129] (2) Preparation of the first agent Hydrophobized gelatin and α-cyclodextrin were weighed, and 0.075 mol / L borate buffer (pH 9.5) was added to prepare the first agent. Table 1 shows the composition of the first agent in each example. For example, in Example 1, 75 mg of gelatin derivative (7.8C10) and 8 mg of α-cyclodextrin (also called "αCD") were dispersed in 1 mL of borate buffer.

[0130] (3) Preparation of the second agent As a crosslinking agent, pentaerythritol-polyethylene glycol ether tetrasuccinimidyl glutarate ("4S-PEG", weight average molecular weight 20,000, NOF Corp.) was prepared. This was dissolved in 0.01 mol / L phosphate buffer (pH 4.0) to prepare the second agent.

[0131] (4) Preparation of adhesive The first and second agents were filled in an ADY W syringe so that the molar ratio (NHS ester of crosslinker) / (primary amino group in the first agent) was 0.5 (50 mol%). This was pushed out and mixed when used. In Table 1, it is listed as "NHS / amine".

[0132] <Evaluation> (Evaluation of swelling) The adhesive was discharged from a W syringe to produce a gel (cured adhesive) with a thickness of 1 mm, which was then hollowed out with a 10 mm diameter punch to prepare a sample.

[0133] Next, the sample (cured adhesive) was transferred to a 50 ml centrifuge tube, 50 ml of physiological saline (containing 25 μ / ml of acid blue) was poured, and the tube was allowed to stand in a 37° C. incubator.

[0134] The mass change was calculated using the following formula from the mass M0 of the sample measured immediately before immersion and the mass M1 after 24 hours of immersion in physiological saline. The lower this value, the less likely the sample is to swell, and the better the adhesive is for application to biological tissue. The measurement results for the adhesives of each Example and Comparative Example are shown in Table 1.

[0135] Mass change (Δ) = |(M1-M0) / M0|

[0136] (Adhesion to biological tissue) In accordance with ASTM-F2392-04R, adhesiveness (compression resistance strength) was evaluated using collagen casing (manufactured by Nippi) as a model tissue for evaluating tissue adhesive strength.

[0137] A pinhole with a diameter of 3 mm was made in a collagen casing with a diameter of 30 mm, and an adhesive was applied to a thickness of 1 mm. This was left to stand at room temperature (23 to 25°C) for 10 minutes, and the pressure resistance strength was measured. The test was performed five times, and the average value was evaluated according to the following criteria. The evaluation results for the adhesives of each Example and Comparative Example are shown in Table 1.

[0138] Evaluation criteria AA: Compressive strength was 14.5 kPa or more. A: The compressive strength was 11.5 kPa or more and less than 14.5 kPa. B: The compressive strength was 8.5 kPa or more and less than 11.5 kPa. C: The compressive strength was 5.5 kPa or more and less than 8.5 kPa. D: The compressive strength was less than 5.5 kPa.

[0139] (viscosity measurement) The viscosity of each of the first agents prepared above was measured at 25° C. using a vibration viscometer "Viscomate VM-100A" (manufactured by Sekonic Corporation). The results are shown in Table 1.

[0140] [Table 1]

[0141] In Table 1, Comparative Example 1 shows the results of measurements made using an adhesive prepared in the same manner as in Example 1, except that the first agent did not contain α-cyclodextrin. Reference Example 1 shows the results of measurements performed in the same manner as above, except that "Duraseal (registered trademark)" was used as the adhesive. "Duraseal" is an adhesive that uses a mixture of a first agent containing a polyethylene glycol ester compound and a phosphate buffer solution and a second agent containing an amino acid solution.

[0142] As shown in Table 1, the adhesive of Example 1, which consists of a first agent containing a gelatin derivative and cyclodextrin and a second agent containing a crosslinking agent for the first agent, is less prone to swelling and has both pressure resistance and viscosity within a practical range compared to the adhesive of Comparative Example 1, which does not contain cyclodextrin, and the adhesive of Reference Example 1.

[0143] Moreover, the adhesive of Example 10, in which the concentration of the gelatin derivative in the first agent was more than 0.050 g / mL and less than 0.150 g / mL, had better pressure resistance than the adhesive of Example 8. Moreover, compared with the adhesive of Example 11, it was less prone to swelling and had better pressure resistance. This tendency was the same regardless of the introduction rate of hydrophobic groups in the gelatin derivative. That is, the adhesive of Example 6, which has an introduction rate of 18.0%, had better pressure resistance than the adhesive of Example 2, and was less likely to swell and had better pressure resistance than the adhesive of Example 7. In addition, the adhesive of Example 14, which has an introduction rate of 51.0%, had better pressure resistance than the adhesive of Example 12, and was less likely to swell and had better pressure resistance than the adhesive of Example 15.

[0144] Moreover, the adhesives of Examples 3 and 9, in which the average introduction rate of hydrophobic groups in the first agent was 10.0 to 50.0%, were less prone to swelling and had better pressure resistance than the adhesive of Example 1. Moreover, they had better pressure resistance than the adhesive of Example 13.

[0145] Furthermore, in the adhesive of Example 5, in which the Cy / HBic in the first part exceeded 1.0, the viscosity of the first part was lower than that of the adhesive of Example 3. Furthermore, in the adhesive of Example 5, in which the Cy / HBic in the first part exceeded 2.0, the viscosity of the first part was lower than that of the adhesive of Example 4.

[0146] In addition, the adhesive of Example 6, in which the concentration of the gelatin derivative in the first agent exceeds 0.075 g / mL, had a better pressure resistance than the adhesive of Example 5. This tendency was similar regardless of the introduction rate of the hydrophobic group in the gelatin derivative. That is, the adhesive of Example 10 had a better pressure resistance than the adhesive of Example 9, and the adhesive of Example 14 had a better pressure resistance than the adhesive of Example 13. [Industrial Applicability]

[0147] The adhesive of the present invention is not easily peeled off because the resulting cured product does not easily swell, and is not easily stressed at the interface, so that the burden on the target tissue is small, and can be used as a tissue adhesive used in surgery, etc. The adhesive of the present invention can also be used as a wound dressing that covers wounds caused by surgery, etc. and promotes wound recovery. The adhesive can also be used as an adhesion inhibitor by applying it to the damaged area after tissue resection, where it acts as a physical barrier to prevent adhesion between surrounding tissues that occurs during the repair process.

[0148] In addition, the adhesive of the present invention is unlikely to swell and can be adjusted to a low viscosity, so it can be applied in the form of a mist using a sprayer. Also, since the viscosity can be easily adjusted using a known thickener, it can be easily used as an adhesive in fields where adhesion after application is important. [Explanation of symbols]

[0149] 10: sprayer, 11: spray tip, 12: extender, 13: applicator, 14: barrel, 15: barrel, 16: syringe holder, 17, 18: plunger, 19: plunger cap, 21: first agent, 22: second agent

Claims

1. A gelatin derivative in which a hydrophobic group is bound to gelatin via an imino group, the derivative being represented by the formula 1: GltnNH-R １ and a first agent containing cyclodextrin, and a second agent containing a crosslinking agent for the gelatin derivative, the hydrophobic group contains a linear alkyl group having 6 to 14 carbon atoms; The adhesive, wherein the cyclodextrin is α-cyclodextrin. (In formula 1, Gltn represents a residue of gelatin, and R １ represents the hydrophobic group, and NH represents the imino group bonded to the residue and the hydrophobic group.

2. 2. The adhesive according to claim 1, wherein the introduction rate of the hydrophobic group in the first part is 5.0 to 80.0 mol %.

3. The adhesive according to claim 1 or 2, wherein the first agent contains a solvent, and the concentration of the gelatin derivative in the first agent is 0.010 to 0.300 g / mL.

4. 4. The adhesive of claim 3, wherein the concentration is greater than 0.050 g / mL and less than 0.150 g / mL.

5. The adhesive according to claim 2, wherein the introduction rate is 10.0 to 50.0 mol %.

6. The adhesive of claim 1 , wherein the hydrophobic group comprises a linear alkyl group having 7 to 12 carbon atoms.

7. 2. The adhesive according to claim 1, wherein the molar ratio of the content of said cyclodextrin to the content of said hydrophobic groups in said first part is 0.1 or more.

8. 8. The adhesive of claim 7, wherein said ratio on a molar basis is greater than 2.6 and less than or equal to 10.

9. The adhesive of claim 1 , wherein the crosslinker is a compound having at least two active ester groups.

10. The adhesive of claim 1 , wherein the gelatin is cold water fish gelatin.

11. A wound dressing comprising the adhesive of claim 1.

12. An anti-adhesion material comprising the adhesive according to claim 1.

13. A hemostatic material comprising the adhesive of claim 1.

14. A sealant comprising the adhesive of claim 1.

15. A spray kit comprising the adhesive of claim 1 and a sprayer for said adhesive.

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